Inflammatory bowel diseases (IBD) is the name given to a group of related diseases affecting the gastrointestinal tract, mainly Crohn's disease and ulcerative colitis, two severe gastrointestinal disorders of high frequency (more than one in 500 Americans has some type of inflammatory bowel disease) and disabling for many patients, and generating a significant burden on the health care system. Patients may have diarrhea, nauseas, vomiting, abdominal cramps, and pain that can be difficult to control. IBDs are characterized by chronic excessive destruction of the colon (in ulcerative colitis) or the small and large bowel (in Crohn's disease), due to the infiltration of the bowel wall by inflammatory infiltrate.
The pathogenesis of IBD involves interactions among local environment microorganisms, genetic susceptibility and the immune system. Several microorganisms, bacteria and viruses, have been implicated as etiologic agents of IBD, however, no evidence of a definite role for one infectious agent has been provided. Recent data suggest some susceptibility genes, yet extensive studies are still required to identify the specific genes responsible for the expression of such diseases. Whereas the nature of both possible infectious agents and genetic alteration remains unclear, great progress has been achieved in understanding the immune mechanisms responsible for the pathogenesis of IBD, particularly Crohn's disease.
CD4+ Th1 cells have been identified as central mediators in the pathogenesis of Crohn's disease, showing restricted but variable TCR repertoire. IFN-γ released by these Th1 cells activates local macrophages to produce pro-inflammatory cytokines and toxic metabolites, in particular TNF-α and nitric oxide (NO), which cause damage to the intestinal epithelium and maintain the transmural inflammation. This chronic abnormal Th1 response is maintained by the abrogation of tolerance to components of the intestinal flora or its products, resulting in an autoimmune-like process. Since a specific host autoantigen has not been identified, IBDs are not genuine autoimmune diseases. However, due to its immune nature, IBD may be viewed as such.
Copolymer 1 (Cop 1, glatiramer acetate or GA), a non-pathogenic synthetic random copolymer composed of the four amino acids: L-Glu, L-Lys, L-Ala, and L-Tyr (hereinafter “Cop 1” or “GA”), is currently an approved drug for the treatment of multiple sclerosis under the name of Copaxone™ (Sela and Teitelbaum, 2001). It is a very well tolerated agent with only minor adverse reactions and high safety profile. Treatment with Cop 1 by ingestion or inhalation is disclosed in U.S. Pat. No. 6,214,791.
Recently it was found that in animal models Cop 1 provides a beneficial effect for several additional disorders. Thus, Cop 1 suppresses the immune rejection manifested in graft versus host disease (GVHD) in case of bone marrow transplantation (Schlegel et al., 1996; U.S. Pat. No. 5,858,964), as well as in graft rejection in case of solid organ transplantation (Aharoni et al., 2001).
WO 01/52878 and WO 01/93893 disclose that Cop 1, Cop 1-related peptides and polypeptides and T cells activated therewith protect CNS cells from glutamate toxicity and prevent or inhibit neuronal degeneration or promote nerve regeneration in the central nervous system and peripheral nervous system. Thus, for example, Cop 1 is under evaluation as a therapeutic vaccine for neurodegenerative diseases such as optic neuropathies and glaucoma (Kipnis and Schwartz, 2002).
Cop 1 and related copolymers and peptides have been disclosed in WO 00/05250 (Aharoni et al., 2000), hereby incorporated by reference in its entirety as if fully disclosed herein, for treating autoimmune diseases. Although colitis is mentioned among the autoimmune diseases, no example or protocol for testing colitis is disclosed in said application.
The available medical treatments for IBD are rather unsatisfactory. A detrimental immune response towards local microorganisms, involving mainly CD4+ Th1 cells, and imbalance between pro-inflammatory and anti-inflammatory reactivity, play a role in the pathogenesis of IBD, particularly in Crohn's disease (CD) (MacDonald et al., 2000; Shanahan, 2001). Current medical treatments for IBD rely on the use of non-specific anti-inflammatory drugs such as corticosteroids, as well as immunosuppressive drugs (Shanahan, 2001). However, these treatments do not modify the disease course but only ameliorate the symptoms, while inducing severe side effects that limit their use. Moreover, significant percentage of the patients are steroid resistance. Hence, there is a real need for new, well-tolerated therapies that effectively induce remission and alter the natural course of the disease. Based on the immunopathological nature of CD, novel immunomodulatory strategies attempt to deviate the CD4+ pathogenic T-cells from Th1 inflammatory to Th2 anti-inflammatory phenotype (Shanahan, 2001; Sandborn and Targan, 2002; Van Deventer, 2000).